Deep brain stimulation (DBS) for psychiatric disorders represents a promising new application of an established medical technology. DBS trials for treatment of psychiatric disorders have demonstrated significant therapeutic benefit. However, precise therapeutic mechanisms, optimal target stimulation sites or regions, and specific axonal pathways responsible for therapeutic benefits have yet to be explicitly defined.
A significant number of psychiatric patients, such as patients diagnosed with treatment-resistant depression (TRD) or obsessive compulsive disorder (OCD) who have undergone multiple pharmacological and behavioral treatments, still remain severely disabled. For these patients, deep brain stimulation (DBS) represents a surgical alternative that has demonstrated encouraging therapeutic results in early stage clinical trials (Lozano, A. M. et al., “Subcallosal cingulate gyrus deep brain stimulation for treatment-resistant depression,” Biol. Psychiatry 64 (6), 461-467 (2008) (hereinafter “Lozano et al., 2008”), the entire contents of which is hereby incorporated by reference herein). However, anatomical target sites or regions to be stimulated and stimulation settings for optimal clinical outcomes remain unclear.
Recent scientific efforts have focused on defining the organization and structural connectivity of neural networks associated with psychiatric disease. Prevailing hypotheses suggest that these therapeutic benefits are brought forth by stimulation-dependent regulation of abnormal network activity (McIntyre, C. C. et al., “Network perspectives on the mechanisms of deep brain stimulation,” Neurobiol. Dis. 38 (3), 329-337 (2010) (hereinafter “McIntyre et al., 2010”), the entire contents of which is hereby incorporated by reference herein). Unfortunately, definition of precise therapeutic mechanisms and optimal target stimulation sites or regions remains restricted by limited characterization of the specific neuronal effects of DBS.
Converging biochemical and functional imaging studies have provided insight into complex cortico-striato-thalamo-cortical (CSTC) networks associated with affective and anxiety disorders. For example, metabolic imaging studies have helped identify cortical and subcortical areas of the brain associated with psychiatric pathologies. Similarly, anatomical tracing work in non-human primates have provided insight into the organization of networks involved with these areas. More recently, diffusion-tensor imaging (DTI) tractography has shown that CSTC projections from the ventral anterior internal capsule/ventral striatum (VC/VS) and subcallosal cingulate white matter, which are the two most actively researched surgical target sites for psychiatric DBS, overlap in multiple regions of the brain associated with antidepressant responses. Anatomical tracing work and DTI tractography studies suggest that while the general trajectory of axonal pathways can overlap, anatomical functional segregation is typically maintained (Gutman, D. A. et al., “A tractography analysis of two deep brain stimulation white matter targets for depression,” Biol. Psychiatry 65 (4), 276-282 (2009) (hereinafter “Gutman et al., 2009”), the entire contents of which is hereby incorporated by reference herein). However, these imaging and anatomical techniques only provide pieces of the complete picture. As such, methodological refinements are required before these techniques can be used to fully describe the neural networks typically associated with psychiatric disease and other disorders and clinical outcomes.
Abnormal activity in the amygdala, thalamus, and orbito-frontal and anterior cingulate cortices has prompted different surgical target sites to be attempted. DBS of the ventral anterior internal capsule/ventral striatum (VC/VS) has already generated long-term improvement in both TRD and OCD patients (Malone, Jr., D. A. et al., “Deep brain stimulation of the ventral capsule/ventral striatum for treatment-resistant depression,” Biol. Psychiatry 65 (4), 267-275 (2009) (hereinafter “Malone, Jr. et al., 2009”), the entire contents of which is hereby incorporated by reference herein). Similarly. DBS of subgenual cingulate white matter has produced sustained improvement in depressive symptoms of TRD patients (Lozano et al., 2008). However, questions still remain on which anatomical target sites or regions and axonal pathways are explicitly responsible for the therapeutic benefits of DBS for psychiatric and other disorders.